Tissue-separating fatty acid adhesion barrier

ABSTRACT

Exemplary embodiments of the present invention provide adhesion barriers having anti-adhesion and tissue fixating properties. The adhesion barriers are formed of fatty acid based films. The fatty acid-based films may be formed from fatty acid-derived biomaterials. The films may be coated with, or may include, tissue fixating materials to create the adhesion barrier. The adhesion barriers are well tolerated by the body, have anti-inflammation properties, fixate, well to tissue, and have a residence time sufficient to prevent post-surgical adhesions.

RELATED APPLICATIONS

The present application is a continuation-in-part of the following: U.S.patent application Ser. No. 11/237,420 entitled “Barrier Layer,” filedon Sep. 28, 2005; U.S. patent application Ser. No. 11/237,264 entitled“A Stand-Alone Film and Methods for Making the Same,” filed on Sep. 28,2005 (now U.S. Pat. No. 8,795,703); U.S. patent application Ser. No.11/978,840 entitled “Coated Surgical Mesh,” filed on Oct. 30, 2007 (nowU.S. Pat. No. 8,574,627); and U.S. patent application Ser. No.12/401,243 entitled “Fatty-Acid Based Particles,” filed on Mar. 10,2009. The contents of the aforementioned patent applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention generally relates to a tissue-separating adhesionbarrier.

BACKGROUND

Medical films are often used in surgical settings as a physical barrierto separate certain organs from adjacent tissues and medical devicesfollowing surgical intervention or blunt dissection to help minimizeadhesion formation post-surgery. For example, SEPRAFILM® (a filmcomposed of chemically modified sugars), a product of GenzymeCorporation of Cambridge, Mass., is used in abdominal or pelvicsurgeries as an implantable treatment intended to reduce the incidence,extent, and severity of postoperative adhesion formation betweendifferent tissues and organs and implantable medical devices such assoft tissue support membranes and mesh, or combinations ofnon-absorbable materials and meshes.

One example of a medical film is described in U.S. Pat. No. 5,017,229.The film of the '229 patent is formed from a water insoluble, gel thatincludes the reaction product of hyaluronic acid (“HA”), a polyanionicpolysaccharide, and an activating agent. The gel described in the '229patent can be provided in the form of an adhesion preventioncomposition, such as a membrane or composition suitable forincorporation into a syringe. The gel is formed into a film by beingcast into a sheet form, extruded, compressed, or allowed to dehydrate ina flat sheet. When modified with polysaccharide, the biodegradable filmforms the above-described SEPRAFILM® adhesion-limiting oradhesion-barrier product made commercially available as a dehydratedbio-dissolvable single layer sheet.

Implantable medical films may be placed at a target site, for example,between two tissues, during surgery. In order to prevent or limitpostoperative adhesion formation, the film should remain at the targetsite for a requisite period of time. For example, some sources havenoted that barrier functionality is required between 3 days and 10 dayspost-surgery (see, Peritoneal Surgery by Gere. S. DiZerega, Alan H.DeCherney, Published by Springer, 2000, page 21). In order to achievethis barrier functionality, a biodegradable film should remain in placeat the target site and it should be absorbed by the body for asufficient period of time to provide barrier functionality post surgerywhen adhesions form.

However, conventional medical films are resorbed into the body tooquickly to provide effective barrier functionality during the time inwhich postoperative adhesion formation typically occurs. For example,many cross-linked carboxymethylcellulose (“CMC”) based films may beabsorbed in-vivo within 7 days.

SUMMARY

As described in more detail below, a fatty-acid based film, such as afilm made of fish oil, constructed with fixating materials, such ascarboxymethylcellulose (“CMC”) or Na-CMC, may be provided to fixate thefilm and prevent migration of the film. Despite inflammatorycharacteristics of CMC and the rapid resorbtion characteristics of CMCand Na-CMC, the adhesion barrier is well-tolerated by the body, isnon-inflammatory, does not migrate from a target site, and does notrequire cross-linking of the CMC. The adhesion barrier of the presentinvention effectively delays resorbtion to an acceptable postimplantation duration (e.g., greater than 7 days). The combination of afatty-acid based film with a fixating material such as CMC or Na-CMCresults in an unexpected synergistic effect. Specifically,non-cross-linked CMC in the presence of the fatty-acid based film doesnot absorb into the body as quickly as cross-linked CMC that is not inthe presence of a fatty acid. As a result, the fixating portion of theadhesion barrier is absorbed into the body at a much slower rate thanother CMC-based films, so that barrier functionality is provided overthe time period that adhesions are likely to form.

In some exemplary embodiments of the invention, the adhesion barrier isin the form of an emulsion. The emulsion may include fatty-acid basedparticles immersed in an emulsion base. The fatty-acid based particlesmay be formed by fragmenting a fatty-acid derived biomaterial associatedwith a cryogenic liquid. The emulsion base may include a mixture of afixating material, such as CMC, with an aqueous-based solution, such as(but not limited to) water, saline, or Ringer's lactate solution.

Exemplary embodiments of the present invention provide adhesion barriersand methods for formulating the adhesion barriers. In accordance withone exemplary embodiment of the present invention, the adhesion barriertakes the form of a fatty acid based film composition. The adhesionbarrier includes a fatty acid based film derived from a cross-linkedfatty acid-derived biomaterial and a tissue fixating coating formed froma material surrounding the fatty acid based film. The tissue fixatingcoating may be applied by any means known in the art.

In accordance with aspects of the present invention, the fattyacid-derived biomaterial is an omega-3 fatty acid. The fattyacid-derived biomaterial may, or may not be, crosslinked. The fattyacid-derived biomaterial may contain at least one lipid or omega-3 fattyacid; for example, the fatty acid-derived biomaterial may be a fish oil.The fish oil may further comprise vitamin E.

In accordance with one exemplary embodiment, the coherent material maybe a polyanionic polysaccharide, such as carboxymethylcellulose (CMC).In accordance with another exemplary embodiment, the coherent materialcomprises a salt of CMC, such as sodium carboxymethylcellulose (Na-CMC).

In accordance with further aspects of the present invention, the fattyacid-derived biomaterial may reduce inflammation associated with thefixating material. In some embodiments, the adhesion barrier does notmigrate from a surgical site of placement, while in further embodiments,the adhesion barrier has a residence time that is sufficient to preventpost-surgical adhesions.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other aspects, embodiments, objects, features andadvantages of the invention can be more fully understood from thefollowing description in conjunction with the accompanying drawings. Inthe drawings like reference characters generally refer to like featuresand structural elements throughout the various figures. The drawings arenot necessarily to scale, emphasis instead being placed uponillustrating the principles of the invention.

FIG. 1 depicts an adhesion barrier in accordance with one exampleembodiment of the present invention.

FIG. 2 is a flow chart depicting an exemplary method for fabricating anexemplary adhesion barrier in accordance with one example embodiment ofthe present invention.

FIG. 3 depicts an adhesion barrier in accordance with one exampleembodiment of the present invention.

FIG. 4 depicts an adhesion barrier in accordance with one exampleembodiment of the present invention.

FIG. 5 depicts an adhesion barrier created as an emulsion in accordancewith one example embodiment of the present invention.

FIG. 6 is a flow chart depicting an exemplary method for fabricating anexemplary adhesion barrier as depicted in FIG. 5.

FIGS. 7A, 7B, 7C, 7D, 7E, 7F, and 7G depict exemplary embodiments of anadhesion barrier coupled with various medical devices.

DETAILED DESCRIPTION

Exemplary aspects and embodiments of the present invention provideadhesion barriers formed from fatty acid-based films or fatty acid-basedparticles. The adhesion barriers have the fixating properties ofmaterials, such as CMC-based films, with an additional unexpectedsynergistic effect, which substantially slows the rate at which thetissue fixating portion of the adhesion barrier is absorbed withoutrequiring crosslinking of the CMC component.

Conventional Films

In some conventional products, hydrophilic tissue fixating componentssuch as poly(ethylene glycol), poly(ethylene oxide), poly(HEMA),poly(N-vinyl pyrrolidone), poly(acrylic acid), carboxymethyl cellulose(CMC), chitosan, etc. are used to provide fixation of the film. Thisfixation can address the problem of film mobility or migration. However,these hydrophilic materials may exhibit appreciable foreign bodyreaction and inflammation, which are undesirable characteristics (see,e.g. European Patent Application EP20020080404).

Further, manufacturing these conventional tissue fixating componentsposes additional challenges. Specifically, the above tissue fixatingcomponents must be chemically crosslinked via functional end groupmodification, or by the use of chemical crosslinking agents, to providesuitable mechanical integrity for handling and insolubility in a wetenvironment. The use of chemical crosslinkers such as gluteraldehyde oraziridines requires the additional step of removing the excesscrosslinking agents by washing or soaking, as these compounds are oftenless biocompatible than the desired hydrogel materials. These additionalsteps add to the expense and difficulty of the manufacturing process.

As noted above, films may be made of a polyanionic polysaccharide andhyaluronic acid. One preferred polyanionic polysaccharide used to make afilm described in the '229 patent is CMC. The film in the '229 patent isformed with HA and CMC (“HA/CMC”). However, it has been noted that themethod for preparing this type of film can be problematic because of theprocedure for removing biologically toxic materials generated in thepreparation (see, e.g., U.S. Patent Application Publication No.2003/0124087). The '087 application notes that the hydration process inan HA/CMC preparation may cause difficulties in treatment and operation.

One alternative to HA/CMC is sodium carboxymethylcellulose (“Na-CMC”).While Na-CMC is effective as an anti-adhesion agent, it is difficult toapply Na-CMC as an anti-adhesion barrier because it is absorbed in thebody too fast to be effective as an adhesion barrier. Fast absorption ofa CMC-based film into the body is problematic, because the film isresorbed before it can act as an effective adhesion barrier. Forexample, HA/CMC films can be absorbed in 7 days, while, as noted above,barrier functionality may be required between 3 days and 10 dayspost-surgery, and in some instances up to 8 weeks of barrierfunctionality is necessary.

Further, films made from salts of CMC, such as Na-CMC, can be difficultor problematic to produce. Producing these films may requireimmobilization of the CMC or stabilization by cross-linking, because theNa and CMC readily dissociate in aqueous media, allowing the CMC todissolve. Cross-linking is the process of chemically joining two or moremolecules with a chemical bond. Cross-linking of CMC can beaccomplished, for example, by irradiating the CMC (see, e.g., Fei etal., Hydragel of Biodegradable Cellulose Derivative. I.Radiation-Induced Cros slinking of CMC, Journal of Applied PolymerScience, vol. 78, pp. 278-283 (2000)).

Without immobilization or stabilization of the CMC by cross-linking, thetransition from solid to liquid significantly reduces the ability ofNa-CMC films to provide effective barrier protection. Cross-linking CMCresults in additional problems. Radiation-induced cross-linking ofunmodified CMC requires the presence of a medium such as water tomobilize the macromolecules and allow for assembly. Solid phaseirradiation of CMC results in degradation of the material by scission ofthe glycosidic bond.

Cross-linked CMC films also have the limit of being quickly resorbedin-vivo, i.e. within 7 days. In addition, CMC films are known to causeinflammation, and may lack adhesiveness and affinity (see, e.g., '087application at paragraphs [0009]-[0013]).

Exemplary Embodiments

In contrast to conventional adhesion barriers, embodiments of thepresent invention provide an adhesion barrier that resides at a targetsite for a sufficient time to provide barrier functionality, does notrequire that the CMC component be cross-linked, and does not provoke asignificant inflammatory response. In accordance with exemplaryembodiments of the present invention, fatty acid-based films or fattyacid-based particles composed of fatty acid-derived biomaterials areused as a resorbable tissue-separating adhesion barrier material.Omega-3 and omega-6 fatty acids are examples of fatty acids that may beobtained from, for example, fish oil. Omega-3 fatty acids includeeicosapentaenoic acid (EPA), docosahexanoic acid (DHA), andalpha-linolenic acid (ALA).

Fatty acid-based barriers composed of fatty acid-derived biomaterialseffectively separate adjacent tissue surfaces, are well tolerated by thebody, and do not exhibit the inflammatory response typical of otherresorbable and permanent implant materials. While CMC-based films adherewell to tissue, CMC-based films readily dissolve in aqueous media inabout 7 days.

Combining fatty acid-based films or particles with fixating materials asdescribed herein results in an effective anti-adhesion barrier withfixating and anti-inflammation properties. Additionally, combining thesetwo types of materials also yields an unexpected synergisticresult—specifically, an adhesion barrier formed from a combination ofCMC and a fatty acid-based film or fatty acid-based particles remains atthe treatment site providing barrier functionality beyond 7 days and forup to 28 days or longer, without crosslinking the CMC. This providessufficient residence time to effectively provide post-surgery barrierfunctionality.

Prior to describing the aspects of the present invention, it should benoted that, as used herein, the term “biocompatible,” means compatiblewith living tissue (e.g., not toxic or injurious). Biocompatiblecompounds may hydrolyze into non-inflammatory components that aresubsequently bio-absorbed by surrounding tissue. Biocompatible compoundsare also referred to herein as “biomaterials.”

Films include substances formed by compressing a gel, or by allowing orcausing a gel to dehydrate, or by curing the gel using heat and/or lightin various ways. In addition, films can be chemically formed inaccordance with processes known by those of ordinary skill in the art.

In addition to films, exemplary embodiments of the present inventioninclude emulsions. An emulsion is a solution of two or more immiscibleliquids. In one exemplary embodiment, the emulsion is formed from anemulsion base mixed with fatty-acid based particles. The fatty-acidbased particles may be derived from a fatty-acid based film.

As used herein, a fatty-acid based material is meant to encompass anyform of material that the fatty acid may take, including films andparticles.

Exemplary Film Embodiments

FIG. 1 depicts an adhesion barrier 100 according to one embodiment ofthe present invention. The adhesion barrier 100 includes a fattyacid-based film 110. The fatty acid-based film 110 may be formed by anyof the methods known in the art. In one embodiment, a crosslinked, fattyacid-derived biomaterial comprises an oil that may be natural or derivedfrom synthetic sources and is used to form the fatty acid-based film110. The crosslinked, fatty acid-derived biomaterial can comprise abiological oil, such as an oil containing at least one lipid or omega-3fatty acid, including a fish oil. The biomaterial further can includevitamin E.

The adhesion barrier 100 also includes a tissue fixating coating 120formed from an fixating material. In one embodiment, the fixatingmaterial is a polyanionic polysaccharide. In another embodiment, thefixating material comprises carboxymethylcellulose (CMC). In yet anotherembodiment, the fixating material comprises sodiumcarboxymethylcellulose (Na-CMC).

FIG. 2 is a flow chart depicting an exemplary method for fabricating theadhesion barrier 100. At step 210, a fatty acid-based film 110 isprepared by one of the methods known in the art. For example, asdescribed in U.S. patent application Ser. No. 11/237,420, which isincorporated herein by reference in its entirely, fish oil may beexposed to heating and/or UV irradiation to form a cross-linked, fattyacid-derived biomaterial such as a gel. The gel may further becompressed or dehydrated to form a film. One of ordinary skill in theart will appreciate that other methodologies may be utilized to form thefatty acid-based film 110, and the present invention is by no meanslimited to the particular methods described in the above-referencedapplication or patent. For example, the fatty acid-based film 110 may beprepared according to the procedure described in U.S. patent applicationSer. No. 11/237,264, which is now U.S. Pat. No. 8,795,703, both of whichare incorporated herein by reference in their entirety.

The oil component may also be hardened, as described in the '420application, in addition to other known methodologies. The step ofhardening can include hardening, or curing, such as by introduction ofUV light, heat, or oxygen, chemical curing, or other curing or hardeningmethod. The purpose of the hardening or curing is to transform the moreliquid consistency of the oil component or oil composition into a moresolid film, while still maintaining sufficient flexibility to allowbending and wrapping of the film as desired.

In some embodiments, the oil component is subjected to a surfacetreatment prior to coating, such as a plasma treatment.

At step 220, the fatty acid-based film 110 is optionally cut to anappropriate size. The final dimensions of the cut fatty acid-based film110 will be dependent on the specific application.

At step 230, a coating solution of tissue fixating material is prepared.In accordance with one exemplary embodiment of the present invention,the coating solution is composed of 0.1%-5% (weight/volume)non-crosslinked high molecular weight Na-CMC with a degree ofsubstitution of 0.65-0.85 (although degrees of substitution below 0.65and up to a theoretical limit of 3 are also acceptable) in a watersolution, such as deionized water or Sterile Water for Injection (SWFI).Optionally, the coating solution may include a plasticizing agent suchas glycerin, propylene glycol, poly ethylene glycol, triacetin citrateor triacetin.

At weight/volume concentrations higher than about 5%, the solutionbecomes a solid-like gel, which may be difficult to work with.Generally, most solutions with a concentration of less than 5% arephysically workable, but care should be taken with the mass loading of,for example, Na-CMC on the surface of the film. If there is too littleNa-CMC it will result in an adhesion barrier with insufficient tissuefixation. Low Na-CMC concentration may require many coating applicationsto achieve to the desired loading. In one embodiment, a weight/volumeconcentration of 2% is used. We have found that a minimum dry loading of1.0 mg/cm² may be used to achieve adequate tissue fixation in-vivo.

A high molecular weight of, for example, 700,000 for Na-CMC may be usedfor the tissue fixating material. In separate evaluations of chitosan,the inventors have found that tissue fixation appears to increase withmolecular weight.

Based on experimental observations, and not being bound by theory, thetissue fixation is due to the hydroscopicity of the coating. Because thehydroscopicity increases with increasing degrees of substitution, allpractical ranges of degrees of substitution are acceptable in thepresent invention. A degree of substitution of between 0.65-1.2 is arange that is practical and readily available

At step 240, the coating solution is applied to the fatty acid-basedfilm 110 using any standard coating method, such as dip coating, spraycoating, brushing, casting, or spin coating. At step 250, the coating isallowed to dry for a suitable amount of time, for example 2-24 hours.Alternatively, an apparatus may be used to accelerate drying throughvarious known methods, so long as the temperature of the coatingsolution is not raised too high (resulting in an aqueous or gelatinouscoating). For example, the film may be vacuum dried.

As an alternative to coating the fatty acid-based film with a fixatingmaterial, the fixating material may be introduced into the original oilor gel before it is formed into a film. An example of an adhesionbarrier in accordance with such an embodiment is shown in FIG. 3. Asshown, the adhesion barrier 300 is formed of a fatty acid-based film310. The adhesion barrier 300 further includes fixating particles 320formed from a fixating material, such as Na-CMC. Such an embodiment maybe formed, for example, by a pressed particle method in which particlesof a fatty acid, such as O3FA, are formed and particles of a fixatingmaterial are formed. The two types of particles are then mixed togetherand pressed to form an adhesion barrier. One of ordinary skill in theart will appreciate other methods for combining two materials togetherto form an intermixed, composite, type of material. All such methods, tothe extent compatible with the materials discussed herein, arecontemplated in the present invention.

FIG. 4 depicts another alternative embodiment of the present invention.In the adhesion barrier depicted in FIG. 4, the adhesion barrier 400 isformed of a fatty acid-based film 410. The fatty acid-based film 410 iscoated with an fixating coating 420 on only one side. Such an adhesionbarrier may be formed, for example, by brushing or spraying the fixatingcoating 420 on only a single side of the fatty-acid based film 410.Other means of coating fatty-acid based film 410 on a single side willbe apparent to one having ordinary skill in the art in light of thepresent disclosure. Alternatively, the fatty acid-based film 410 may becoated on two or more surfaces without entirely surrounding the fattyacid-based film. Accordingly, tissue fixation can be achieved on one orboth sides of the fatty acid-based film.

Exemplary Emulsion Embodiments

FIG. 5 depicts another alternative embodiment of the present invention.The adhesion barrier 500 depicted in FIG. 5 is an emulsion of fatty-acidbased particles 510 mixed with an emulsion base 520, such as a CMC andwater mixture.

The fatty-acid based particles 510 may be formed by associating across-linked fatty acid-derived biomaterial with a cryogenic liquid andfragmenting the biomaterial/cryogenic liquid composition, such thatfatty acid particles are formed. In one embodiment, the source of thecross-linked fatty acid-derived biomaterial is a fish oil, e.g., a fishoil that has been heated or exposed to UV-radiation in order to crosslink some or all of the fatty acids of the fish oil.

In one embodiment, associating the cross-linked fatty acid-derivedbiomaterial with a cryogenic liquid includes suspending, submerging, andsurrounding the cross-linked fatty acid-derived biomaterial. In anotherembodiment, the cryogenic liquid comprises liquid nitrogen. Thecross-linked fatty acid-derived biomaterial/cryogenic liquid compositioncan be fragmented using one or more of grinding, shearing, shocking,shattering, granulating, pulverizing, shredding, crushing, homogenizing,sonicating, vibrating, and/or milling. The cryogenic liquid can besubstantially removed by evaporation, either before fragmentation orafter the particles are formed.

The cross-linked, fatty acid-derived biomaterial can comprise an oilthat may be natural or derived from synthetic sources. The cross-linked,fatty acid-derived biomaterial can comprise a biological oil, such as anoil containing at least one lipid or omega-3 fatty acid, such as a fishoil. The fish oil further can include vitamin E. As described herein,the fish oil is exposed to heating and/or UV irradiation to form across-linked, fatty acid-derived biomaterial (e.g., gel). In oneembodiment, before being associated with a cryogenic liquid, thecross-linked material is in the form of a film. In another embodiment,the film is coarsely ground prior to association with the cryogenicliquid.

When the cross-linked, fatty acid-derived biomaterial is in the form ofa film, a therapeutic agent can be loaded into the film before particleformation, during particle formation, or after particle formation. Instill another embodiment, the film is coated with a therapeuticagent/solvent mixture. The therapeutic agent can be dissolved in asolvent, such as methanol or ethanol, and the therapeutic agent/solventmixture can be applied to the film, e.g., by dipping or spraying.

Once prepared, the fatty-acid based particles 510 can be soaked in atherapeutic agent dissolved in solvent, such as hexane, isopar, water,ethanol, methanol, proglyme, methylene chloride, acetonitrile, acetone,or MEK, and the solvent can be substantially removed, resulting in fattyacid particles associated with a therapeutic agent.

The therapeutic agent can be one or more of an antioxidant,anti-inflammatory agent, anti-coagulant agent, drug to alter lipidmetabolism, anti-proliferative, anti-neoplastic, tissue growthstimulant, functional protein/factor delivery agent, anti-infectiveagent, imaging agent, anesthetic agent, chemotherapeutic agent, tissueabsorption enhancer, anti-adhesion agent, germicide, analgesic,antiseptic, or pharmaceutically acceptable salts, esters, or prodrugsthereof. In particular embodiments, the therapeutic agent is selectedfrom the group consisting of rapamycin, marcaine, Cyclosporine A(referred to herein as “CSA”), ISA 247 (referred to herein as “ISA”) andrifampicin.

In one embodiment, the mean particle size of the fatty-acid basedparticles 510 is in the range of about 1 micron to about 50 microns,e.g., 1 micron to about 10 microns. In another embodiment, the particleshave a distribution of size of about 1-20 μm (v,0.1), 21-40 μm (v,0.5),and 41-150 μm (v,0.9).

The emulsion base 520 is a liquid or aqueous-based solution which doesnot combine with the fatty-acid based particles 510 when mixed. In oneexample, the emulsion base is a CMC and water mixture. Other suitableemulsion bases include, but are not limited to, saline solutions andRinger's lactate solution. The emulsion base may include a tissuecoherent material.

FIG. 6 is a flowchart depicting an exemplary method for creating theadhesion barrier of FIG. 5. At step 610, an emulsion base solution isprepared. In one example, an emulsion base solution comprising a CMC andwater mixture (4.2% w/w) was prepared using a Silverson Homogenizer(8kRPM) and was allowed to swell at room temperature overnight.

At step 620, fatty-acid based film particles are prepared, as describedabove. Specifically, the fatty-acid based particles may be formed by:(a) combining a cross-linked, fatty acid-derived biomaterial (e.g., across-linked fish oil) and a therapeutic agent to form a firstcomposition; (b) submerging, surrounding, or suspending the compositionin a cryogenic liquid (c) fragmenting the composition; and (d)optionally removing the dispersing media.

The dispersing media may comprise a solvent that will not dissolve thetherapeutic agent or the cross-linked, fatty acid-derived biomaterial.In still another embodiment, the solvent is hexane, Isopar, water,ethanol, methanol, Proglyme, methylene chloride, acetonitrile, acetone,MEK, liquid nitrogen, and other solvents that do not fully dissolve thetherapeutic agent. In another embodiment, the cross-linked, fattyacid-derived biomaterial is in the form of a film. In anotherembodiment, the film is coarsely ground prior to association with thetherapeutic agent.

The starting materials may be fragmented into solid particles byimpacting the starting materials with a rod that is magneticallyactuated. For example, a Spex Certiprep Cryomill (model 6750) can beused to fragment solid materials into particles. The composition can beplaced in an enclosed vial, and a rod like impactor is enclosed in thevial. The vial is maintained at cryogenic temperatures, and the rod israpidly oscillated in the vial by means of magnets.

In one example, fish oil was partially cured then cast into a thin film6 mil (0.006″) in thickness. The thin film was UV cured for 15 minutes,heat cured in an oven at 93° C. for 24 hours, and then cooled for 24hours. The cured fish oil films were ground with a mortar and pestle inthe presence of liquid nitrogen. The thin film particles were furtherground using a cryogrinder for 8 cycles. In each of the 8 cycles, thecryogrinder was on for 2 minutes at speed 15 and off for 2 minutes. Theparticles were stored at—20° C.

At step 630, the particles are homogenized with a fatty acid in order toform a fatty acid-based solution. In one exemplary embodiment, 1 gram ofthe particles was homogenized with 8 grams of fish oil using theSilverson Homogenizer (8kRPM) until all the particles were evenlydispersed.

At step 640, the emulsion base is mixed with the fatty acid-basedsolution to form an emulsion. In one example, the fatty acid-basedsolution was mixed with 31 grams of 4.2% CMC gel (after swelling) usingthe Silverson Homogenizer (8kRPM).

At step 650, the emulsion is sterilized. For example, the emulsion maybe e-beam sterilized at a dose of 23 kGy.

An exemplary emulsion was prepared following steps 610-650. Theresulting emulsion had a viscosity in the range of 50,000-75,000 cP.

It should also be noted that the present description makes use of meshesas an example of a medical device that can be combined with the adhesionbarriers of the present invention. However, the present invention is notlimited to use with meshes. Instead, any number of other implantablemedical devices can be combined with the adhesion barriers in accordancewith the teachings of the present invention. Such medical devicesinclude catheters, grafts, balloons, prostheses, stents, other medicaldevice implants, and the like. Furthermore, implantation refers to bothtemporarily implantable medical devices, as well as permanentlyimplantable medical devices.

FIGS. 7A, 7B, 7C, 7D, 7E, 7F, and 7G illustrate some of the forms ofmedical devices mentioned above in combination with the adhesionbarriers 710 of the present invention. FIG. 7A shows a graft 720 withthe adhesion barrier 710 coupled or adhered thereto. FIG. 7B shows acatheter balloon 730 with the adhesion barrier 710 coupled or adheredthereto. FIG. 7C shows a stent 740 with the adhesion barrier 710 coupledor adhered thereto. FIG. 7D illustrates a stent 750 in accordance withone embodiment of the present invention. The stent 750 is representativeof a medical device that is suitable for having particles appliedthereon to effect a therapeutic result. The stent 750 is formed of aseries of interconnected struts having gaps formed therebetween. Thestent 750 is generally cylindrically shaped. FIG. 7E illustrates acoated surgical mesh (coated with the adhesion barrier 710), representedas a biocompatible mesh structure 760, in accordance with one embodimentof the present invention. The biocompatible mesh structure 760 isflexible, to the extent that it can be placed in a flat, curved, orrolled configuration within a patient. The biocompatible mesh structure760 is implantable, for both short term and long term applications.Depending on the particular formulation of the biocompatible meshstructure 760, the biocompatible mesh structure 760 will be presentafter implantation for a period of hours to days, or possibly months, orpermanently. FIG. 7F illustrates an adhesion barrier 710 in the form ofa stand alone film in accordance with one embodiment of the presentinvention. The adhesion barrier 710 is flexible, to the extent that itcan be placed in a flat, curved, or rolled, configuration within apatient. The adhesion barrier 710 is implantable, for both short termand long term applications. Depending on the particular formulation ofthe adhesion barrier 710, the adhesion barrier 710 will be present afterimplantation for a period of hours to days, or possibly months. FIG. 7Gillustrates the adhesion barrier 710 and a medical device in the form ofa mesh 770. In the figure, the adhesion barrier 710 and mesh 770 areshown in exploded view. In instances of the mesh 770, it can be usefulto have one side of the mesh support a rougher surface to encouragetissue in-growth, and the other side of the mesh with an anti-adhesion,anti-inflammatory, and/or non-inflammatory surface to prevent the meshfrom injuring surrounding tissue or causing inflammation. The couplingof the adhesion barrier 710 with the mesh 770 achieves such a device.Each of the medical devices illustrated, in addition to others notspecifically illustrated or discussed, can be combined with the adhesionbarrier 710 using the methods described herein, or variations thereof.Accordingly, the present invention is not limited to the exampleembodiments illustrated. Rather the embodiments illustrated are merelyexample implementations of the present invention.

In use, the adhesion barrier of the present invention is applied at atarget site, for example a surgical site. The adhesion barrier may beapplied between two areas of interest—for example, between tissues,organs, meshes, or other non-absorbable materials. The fixatingproperties of the adhesion barrier cause the adhesion barrier to fixateto the areas of interest so that the barrier does not migrate from thetarget site.

Post surgery, the surgical incision is closed and the target site isallowed to heal. Under normal conditions without use of an adhesionbarrier, adhesions would begin to form between the areas of interest.For example, fibrous bands may form between tissues and organs 3 to 10days post surgery. When the adhesion barrier is present at the targetsite, the adhesion barrier prevents adhesions from forming. Because theadhesion barrier fixates sufficiently to the areas of interest, andbecause the adhesion barrier is absorbed into the body relativelyslowly, the adhesion barrier is in place at the target site at the timeadhesions would otherwise form.

After barrier functionality is no longer needed, the adhesion barrier isabsorbed into the body.

Exemplary illustrative embodiments are described below.

Example 1 Bench Top Force of Detachment Non Sterile Samples

A coating solution composed of 2% (w/v) non-crosslinked high molecularweight Na-CMC with a degree of substitution of 0.65 (Sigma) in deionizedwater was applied to 15 one inch square fatty acid-based films andallowed to dry to form adhesion barriers in accordance with embodimentsof the present invention. The adhesion barriers were placed on freshlyslaughtered bovine intestine that was rinsed in tap water prior totesting. The adhesion barriers were allowed to remain on the tissue for3 minutes before testing. A Chatillon gauge was use to measure the forceof detachment in the direction parallel to the plane of adhesion betweenthe adhesion barriers and the tissue. The maximum force measured on theChatillon gauge for each sample was collected. 15 uncoated fattyacid-based films were measured for reference. The uncoated films had amean force of detachment of 0.08 lbf. In contrast, the coated filmsforming adhesion barriers in accordance with embodiments of the presentinvention had a mean force detachment of 0.54 lbf.

Example 2 In-Vivo Results of a Fatty Acid-CMC Film in Minimizing Tissueto Tissue Adhesions

Test samples of an adhesion barrier in accordance with exemplaryembodiments of the present invention were produced using the methodsdescribed above in Example 1. The CMC was not modified to enhancecrosslinking and no crosslinking facilitators were employed. The testsamples were implanted in a rabbit sidewall model of adhesionprevention. Samples were sterilized using an electron beam at a dose of22.5 kGy. The cecum was fully abraded to produce punctate bleeding and a3×5 cm section of the peritoneum was excised. This model yields denseadhesions in untreated animals. A 4×6 cm O3FA film coated with CMC wasplaced on the peritoneal defect with the coated side in direct contactwith the sidewall. At 28 days post implant, the rabbits were sacrificedand the area of adhesions was graded.

Four rabbits were maintained as a control group with no treatment. Fiverabbits were treated with the adhesion barriers. In the four controlsubjects, the mean area of adhesion was 100%. In the experimentalsubjects having the adhesion barriers, the mean area of adhesion was 8%.

As noted, no crosslinking facilitators were employed in this example.Electron beams are known to degrade previous solid CMC films which willresult in faster absorption in-vivo. However, despite the use of e-beamsterilization, the results from Example 2 show that the adhesionbarriers remained tissue coherent for at least 28 days.

Example 3

Crosslinking via radiation exposure is a method that can be used toincrease the in-vivo residence time of aqueous CMC compositions. Toevaluate the effect of radiation exposure on dry CMC films, a solutioncomposed of 2% (w/v) Na-CMC with a degree of substitution of 0.7(Hercules) in SWFI was diluted with SWFI in a solution:SWFI ratio of5:2. The dilute solution was poured into a Teflon coated well plate andallowed to dry at room temperature for 24 hours, resulting in a thinsolid film of CMC. The film was cut into several square pieces that werepackaged separately. Several pieces were irradiated using a 10 MeVelectron beam source at a dose of 22.5 kGy. Irradiated andnon-irradiated samples were submerged in separate aluminum pans ofdeionized water and evaluated for solubility and maintenance/loss ofstructure. If the CMC films were crosslinked by the exposure toradiation, hydration of the films should result is some swelling withmaintenance of the original square geometry. In contrast, bothirradiated and non-irradiated films swelled and lost structure withinabout 10 minutes and were no longer detectable as solids or gels by 30minutes, indicating that the CMC was fully mobile (not crosslinked orotherwise immobilized via chemical bonding) in both samples. The CMCsolutions in the pans were allowed to evaporate over 48 hours at ambientroom temperature, yielding uniformly thin solid films of CMC thatconformed to the circular pan geometry at the bottom of the pan. Fulland equal solubility of exposed and non-exposed CMC films is evidencethat the electron beam exposure did not constructively limit themobility of (i.e. crosslink) the CMC material.

To further evaluate the effect of radiation crosslinking on CMC in thepresence of O3FA, two test samples of an adhesion barrier in accordancewith exemplary embodiments of the present invention were produced usingthe methods described above in Example 1. Adhesion Barrier 1 was exposedto a 10 MeV electron beam source with a dose of 22.5 kGy. AdhesionBarrier 2 was not exposed to electron beam radiation. The adhesionbarriers were weighed and exposed to 200 mL of deionized water, withvisual evaluation at 2, 5, and 69 hours. The adhesion barriers were thenvacuum dried for 2 hours at 25 mTorr. Measurements and observations areprovided below in Table 1.

TABLE 1 Mass/ Film Initial Observation Observation Observation FinalArea E-beam Area Mass after 2 h in after 5 h in after 69 h in Mass LostSample Exposure [cm²] [mg] DI water DI water DI water [mg] [mg/cm²] 1Yes 27.72 499.1 Gel layer Gel layer No gel layer 438.9 2.17 thickness ofthickness of 3 mm 1 mm 2 No 23.18 367.3 Gel layer Gel layer No gel layer317.6 2.14 thickness of thickness of 3 mm 1 mm

The authors had previously determined that the coating method employedyields a coating mass density of 2.28+/−0.11 mg/cm² (mean+/−1σ, n=12).Both adhesion barriers have mass losses (2.17 and 2.14 mg/cm²,respectively) that support the conclusion that the coating is fullysoluble in DI water, and therefore not crosslinked or otherwiseimmobilized. Visual observations support this conclusion.

CMC in the presence of O3FA took between 5 and 69 hours to fullydissolve in DI water, whereas CMC only films were fully dissolved in 30minutes. The presence of O3FA appears to slow the dissolution of CMC inDI water. This is independent of irradiation with electron beam.

Example 4

A coating solution composed of 2% (w/v) Na-CMC with a degree ofsubstitution of 0.7 (Hercules) and 1% glycerin in SWFI was prepared. Thecoating solution was applied to several fatty acid-based films and wasallowed to dry to form adhesion barriers. The adhesion barriersexhibited excellent handling, as the coating was well plasticized. Theadhesion barriers were sterilized using an electron beam at a dose of22.5 kGy and implanted in a rabbit sidewall model of adhesions. Thececum was fully abraded to produce punctate bleeding and a 3×5 cmsection of the peritoneum as excised. A 4×6 cm film coated with CMC wasplaced on the peritoneal defect with the coated side in direct contactwith the sidewall. At 28 days post implant, the rabbits were sacrificedand the area of adhesions was graded.

Four rabbits were maintained as a control group with no treatment. Fiverabbits were treated with the adhesion barriers. In the four controlsubjects, the mean area of adhesion was 100%. In the experimentalsubjects having the adhesion barriers, the mean area of adhesion was 8%.

The results show that, in this study, the addition of a plasticizingagent had no effect on the efficacy of the adhesion barriers comprisingan O3FA-CMC film, as the adhesion barrier did not migrate from the siteof treatment. The results of this study show that the plasticizedadhesion barrier was tissue fixating for at least 28 days.

Example 5 O3FA Film with Tissue Fixating Chitosan Coating

A coating solution composed of 4% (w/v) ChitoPharm S(MW=50,000-1,000,000, Cognis) in a 1% acetic acid solution was dialyzedusing a Fisherbrand regenerated cellulose dialysis tubing membrane witha molecular weight cut off of 3,500. The final coating solution pH was6.27. The coating was applied to several 4×6 cm O3FA films and evaluatedin a rabbit sidewall model of adhesion prevention. Samples weresterilized using E-beam at a dose of 22.5 kGy. The cecum was fullyabraded to produce punctate bleeding and a 3×5 cm section of theperitoneum was excised. This model yields dense adhesions in untreatedanimals. The 4×6 cm films coated with chitosan were placed on theperitoneal defect with the coated side in direct contact with thesidewall. At 28 days post implant, the rabbits were sacrificed and thearea of adhesions was graded. Results are shown in the table below.

Mean Area of Adhesions Group Description n (%) 1 control, no treatment 4100 2 Chitosan Coating 5 34

Example 6 Emulsion

An adhesion barrier in the form of an emulsion, as depicted in FIG. 5,was prepared according to the procedure described in FIG. 6. Samples ofthe emulsion were stored at 4° C. until being tested.

Test samples of the emulsion were examined in a rabbit sidewall model toassess adhesion prevention. The cecum was fully abraded to producepunctate bleeding and a 3×5 cm section of the peritoneum was excised.This model yields dense adhesions in untreated animals. 10 mL of theemulsion was applied to the peritoneal and sidewall injuries. At 28 dayspost implant, the rabbits were sacrificed and the area of adhesions wasgraded.

Results showed that three of the six animals tested had no adhesionformation (area=0%). The remaining three that did form adhesions had atenacity of only 1, indicating that the adhesions were mild and easilydissectible. The average area of adhesion coverage was 28.3% and theaverage tenacity score was 0.5. These results contrasted that of thecontrol, untreated animal, as detailed in the table below.

Mean Area of Group Description n Adhesions (%) Tenacity 1 Control, notreatment 4 100 2.75 2 Emulsion 6 28.3 0.5Biocompatibility and In-Vivo Performance

The process of making the fatty acid-based biomaterials as described inaccordance with the present invention led to some unexpected chemicalprocesses and characteristics in view of traditional scientific reportsin the literature about the oxidation of oils (J. Dubois et al. JAOCS.1996, Vol. 73, No. 6, pgs 787-794. H. Ohkawa et al., AnalyticalBiochemistry, 1979, Vol. 95, pgs 351-358; H. H. Draper, 2000, Vol. 29,No. 11, pgs 1071-1077). Oil oxidation has traditionally been of concernfor oil curing procedures due to the formation of reactive byproductssuch as hydroperoxides and alpha-beta unsaturated aldehydes that are notconsidered to be biocompatible (H. C. Yeo et al. Methods in Enzymology.1999, Vol. 300, pgs 70-78; S-S. Kim et al. Lipids. 1999, Vol. 34, No. 5,pgs 489-496.). However, the oxidation of fatty acids from oils and fatsare normal and important in the control of biochemical processesin-vivo. For example, the regulation of certain biochemical pathways,such as to promote or reduce inflammation, is controlled by differentlipid oxidation products (V. N. Bochkov and N. Leitinger. J. Mol. Med.2003; Vol. 81, pgs 613-626). Additionally, omega-3 fatty acids are knownto be important for human health and specifically EPA and DHA haveanti-inflammatory properties in-vivo. However, EPA and DHA are notanti-inflammatory themselves, but it is the oxidative byproducts theyare biochemically converted into that produce anti-inflammatory effectsin-vivo (V. N. Bochkov and N. Leitinger, 2003; L. J. Roberts II et al.The Journal of Biological Chemistry. 1998; Vol. 273, No. 22, pgs13605-13612.). Thus, although there are certain oil oxidation productsthat are not biocompatible, there are also several others that havepositive biochemical properties in-vivo (V. N. Bochkov and N. Leitinger,2003; F. M. Sacks and H. Campos. J Clin Endocrinol Metab. 2006; Vol. 91,No. 2, pgs 398-400; A. Mishra et al. Arterioscler Thromb Vasc Biol.2004; pgs 1621-1627.). Thus, by selecting the appropriate processconditions, an oil-derived cross-linked hydrophobic biomaterial can becreated and controlled using oil oxidation chemistry with a finalchemical profile that will have a favorable biological performancein-vivo.

The process of making an oil-derived hydrophobic non-polymericbiomaterial in accordance with the present invention leads to a finalchemical profile that is biocompatible, minimizes adhesion formation,acts as a tissue separating barrier, and is non-inflammatory withrespect to the material chemistry and the products produced uponhydrolysis and absorption by the body in-vivo. These properties are dueto several unique characteristics of the fatty acid-derived biomaterialsin embodiments of the present invention.

One aspect of the present invention is that no toxic, short-chainedcross-linking agents (such as glutaraldehyde) are used to form theoil-derived biomaterials and thus the adhesion barrier of the invention.It has been previously demonstrated in the literature that short chaincross-linking agents can elute during hydrolysis of biodegradablepolymers and cause local tissue inflammation. The process of creatingoil-derived biomaterials does not involve cross-linking agents becausethe oil is cured into a coating using oil autoxidation orphoto-oxidation chemistry. The oxidation process results in theformation of carboxyl and hydroxyl functional groups that allow for theoil-derived biomaterial to become hydrated very rapidly and becomeslippery, which allows for frictional injury during and afterimplantation to be significantly reduced and/or eliminated. The methodsof making the oil-derived biomaterials described in embodiments of thepresent invention allow the alkyl chains of the fatty acid, glycerideand other lipid byproducts present in the coating to be disordered,which creates a coating that is flexible and aids in handling of thematerial while being implanted.

There are several individual chemical components of the presentinventive materials that aid in biocompatibility and the low tonon-inflammatory response observed in-vivo. One aspect of exemplaryembodiments of the present invention is that the process of creating anoil-derived biomaterial used to form the adhesion barrier as describedherein results in low to non-detectable amounts of oxidized lipidbyproducts of biocompatibility concern, such as aldehydes. Theseproducts are either almost completely reacted or volatilized during thecuring process as described in exemplary embodiments of the presentinvention. The process of creating an oil-derived biomaterial largelypreserves the esters of the native oil triglycerides and forms esterand/or lactone cross-links, which are biocompatible (K. Park et al.,1993; J. M. Andersen, 1995).

In addition to general chemical properties of an oil-derived biomaterialthat assists in its biocompatibility, there are also specific chemicalcomponents that have positive biological properties. Another aspect isthat the fatty acid chemistry produced upon creation of an oil-derivedbiomaterial is similar to the fatty acid chemistry of tissue. Thus, asfatty acids are eluting from the adhesion barrier they are not viewed asbeing “foreign” by the body and do not cause an inflammatory response.In fact, C14 (myristic) and C16 (palmitic) fatty acids present in theadhesion barrier have been shown in the literature to reduce productionof α-TNF, an inflammatory cytokine. The expression of α-TNF has beenidentified as one of the key cytokines responsible for “turning on”inflammation in the peritoneal cavity after hernia repair, which canthen lead to abnormal healing and adhesion formation (Y. C. Cheong et.al., 2001). α-TNF is also an important cytokine in vascular injury andinflammation (D. E. Drachman and D. I. Simon, 2005; S. E. Goldblum,1989), such as vascular injury caused during a stent deployment. Inaddition to the fatty acids just specified, there have also beenadditional oxidized fatty acids identified that have anti-inflammatoryproperties. Another component identified from the fatty acid-derivedbiomaterials as described herein are delta-lactones (i.e., 6-memberedring cyclic esters). Delta-lactones have been identified as havinganti-tumor properties (H. Tanaka et. al. Life Sciences 2007; Vol. 80,pgs 1851-1855).

The components identified herein are not meant to be limiting in scopeto the present invention, as changes in starting oil composition and/orprocess conditions can invariably alter the fatty acid and/or oxidativebyproduct profiles and can be tailored as needed depending on theintended purpose and site of application of the fatty acid-derivedbiomaterial.

In summary, the biocompatibility and observed in-vivo performance offatty acid-derived biomaterials that form the adhesion barrier describedherein are due to the elution of fatty acids during hydrolysis of thematerial during implantation and healing and are not only beneficial asto prevent a foreign body response in-vivo due to the similarity of thefatty acid composition of the material to native tissue (i.e., abiological “stealth” coating), but the specific fatty acids and/or otherlipid oxidation components eluting from the coating aid in preventingforeign body reactions and reducing or eliminating inflammation, whichleads to improved patient outcomes. Additionally, the fatty acid andglyceride components eluted from the fatty acid-derived biomaterialforming the fatty acid-based film of the adhesion barrier are able to beabsorbed by local tissue and metabolized by cells, in, for example, theCitric Acid Cycle (M. J. Campell, “Biochemistry: Second Edition.” 1995,pgs 366-389). Hence, the fatty acid-derived biomaterial described inaccordance with the present invention is also bioabsorbable.

Methods of Treatment Using the Adhesion Barrier

In general, four types of soft tissue are present in humans: epithelialtissue, e.g., the skin and the lining of the vessels and many organs;connective tissue, e.g., tendons, ligaments, cartilage, fat, bloodvessels, and bone; muscle, e.g., skeletal (striated), cardiac, orsmooth; and nervous tissue, e.g., brain, spinal cord and nerves. Theadhesion barrier in accordance with the present invention can be used totreat injury to these soft tissue areas. Thus, in one embodiment, theadhesion barrier of the present invention can be used for promotion ofproliferation of soft tissue for wound healing. Furthermore, followingacute trauma, soft tissue can undergo changes and adaptations as aresult of healing and the rehabilitative process. Such changes include,but are not limited to, metaplasia, which is conversion of one kind oftissue into a form that is not normal for that tissue; dysplasia, withis the abnormal development of tissue; hyperplasia, which is excessiveproliferation of normal cells in the normal tissue arrangement; andatrophy, which is a decrease in the size of tissue due to cell death andresorption or decreased cell proliferation. Accordingly, the fattyacid-derived biomaterial of the present invention can be used for thediminishment or alleviation of at least one symptom associated with orcaused by acute trauma in soft tissue.

In accordance with one exemplary embodiment of the present invention, asdescribed below, the adhesion barrier can be used to prevent tissueadhesion. The tissue adhesion can be, for example, a result of bluntdissection. Blunt dissection can be generally described as dissectionaccomplished by separating tissues along natural cleavage lines withoutcutting. Blunt dissection is executed using a number of different bluntsurgical tools, as is understood by those of ordinary skill in the art.Blunt dissection is often performed in cardiovascular, colo-rectal,urology, gynecology, upper GI, and plastic surgery applications, amongothers.

After the blunt dissection separates the desired tissues into separateareas, there is often a need to maintain the separation of thosetissues. In fact, post surgical adhesions can occur following almost anytype of surgery, resulting in serious postoperative complications. Theformation of surgical adhesions is a complex inflammatory process inwhich tissues that normally remain separated in the body come intophysical contact with one another and attach to each other as a resultof surgical trauma.

It is believed that adhesions are formed when bleeding and leakage ofplasma proteins from damaged tissue deposit in the abdominal cavity andform what is called a fibrinous exudate. Fibrin, which restores injuredtissues, is sticky, so the fibrinous exudate may attach to adjacentanatomical structures in the abdomen. Post-traumatic or continuousinflammation exaggerates this process, as fibrin deposition is a uniformhost response to local inflammation. This attachment seems to bereversible during the first few days after injury because the fibrinousexudates go through enzymatic degradation caused by the release offibrinolytic factors, most notably tissue-type plasminogen activator(t-PA). There is constant play between t-PA and plasminogen-activatorinhibitors. Surgical trauma usually decreases t-PA activity andincreases plasminogen-activator inhibitors. When this happens, thefibrin in the fibrinous exudate is replaced by collagen. Blood vesselsbegin to form, which leads to the development of an adhesion. Once thishas occurred, the adhesion is believed to be irreversible. Therefore,the balance between fibrin deposition and degradation during the firstfew days post-trauma is critical to the development of adhesions(Holmdahl L. Lancet 1999; 353: 1456-57). If normal fibrinolytic activitycan be maintained or quickly restored, fibrous deposits are lysed andpermanent adhesions can be avoided. Adhesions can appear as thin sheetsof tissue or as thick fibrous bands.

Often, the inflammatory response is also triggered by a foreignsubstance in vivo, such as an implanted medical device. The body seesthis implant as a foreign substance, and the inflammatory response is acellular reaction to wall off the foreign material. This inflammationcan lead to adhesion formation to the implanted device; therefore amaterial that causes little to no inflammatory response is desired.

Thus, adhesion barrier of the present invention may be used as a barrierto keep tissues separated to avoid the formation of adhesions, e.g.,surgical adhesions. Application examples for adhesion prevention includeabdominal surgeries, spinal repair, orthopedic surgeries, tendon andligament repairs, gynecological and pelvic surgeries, and nerve repairapplications. The adhesion barrier may be applied over the trauma siteor wrapped around the tissue or organ to limit adhesion formation. Theaddition of therapeutic agents to the fatty acid-derived biomaterialused in these adhesion prevention applications can be utilized foradditional beneficial effects, such as pain relief or infectionminimization. Other surgical applications of adhesion barrier mayinclude using a stand-alone film as a dura patch, buttressing material,internal wound care (such as a graft anastomotic site), and internaldrug delivery system. The adhesion barrier may also be used inapplications in transdermal, wound healing, and non-surgical fields. Theadhesion barrier may be used in external wound care, such as a treatmentfor burns or skin ulcers. The adhesion barrier may be used without anytherapeutic agent as a clean, non-permeable, non-adhesive,non-inflammatory, anti-inflammatory dressing, or the adhesion barriermay be used with one or more therapeutic agents for additionalbeneficial effects. The adhesion barrier may also be used as atransdermal drug delivery patch when the fatty acid-derived biomaterialis loaded or coated with one or more therapeutic agents.

The process of wound healing involves tissue repair in response toinjury and it encompasses many different biologic processes, includingepithelial growth and differentiation, fibrous tissue production andfunction, angiogenesis, and inflammation. Accordingly, the adhesionbarrier provides an excellent material suitable for wound healingapplications.

Combining fatty acid-based films with tissue fixating materials resultsin an effective adhesion barrier with fixating and anti-inflammationproperties. The resulting adhesion barrier is well-tolerated by thebody, reduces adhesions post-surgery, and does not migrate from thetarget site due to the film's fixating properties. Further, the adhesionbarrier is absorbed into the body relatively slowly as compared toconventional CMC-based films, and so facilitates tissue adhesion betweenthe adhesion barrier and the site of treatment for up to 28 days. Thisprovides sufficient residence time to effectively provide post-surgerybarrier functionality. Further, combining fatty acid-based films withtissue fixating materials may avoid the need to crosslink the tissuefixating material, reducing the cost and complexity of manufacturing thefilm.

Numerous modifications and alternative embodiments of the presentinvention will be apparent to those skilled in the art in view of theforegoing description. Accordingly, this description is to be construedas illustrative only and is for the purpose of teaching those skilled inthe art the best mode for carrying out the present invention. Details ofthe structure can vary substantially without departing from the spiritof the invention, and exclusive use of all modifications that comewithin the scope of the appended claims is reserved. It is intended thatthe present invention be limited only to the extent required by theappended claims and the applicable rules of law.

All literature and similar material cited in this application,including, patents, patent applications, articles, books, treatises,dissertations and web pages, regardless of the format of such literatureand similar materials, are expressly incorporated by reference in theirentirety. In the event that one or more of the incorporated literatureand similar materials differs from or contradicts this application,including defined terms, term usage, described techniques, or the like,this application controls.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described inany way.

While the present inventions have been described in conjunction withvarious embodiments and examples, it is not intended that the presentteachings be limited to such embodiments or examples. On the contrary,the present inventions encompass various alternatives, modifications,and equivalents, as will be appreciated by those of skill in the art.

The claims should not be read as limited to the described order orelements unless stated to that effect. It should be understood thatvarious changes in form and detail can be made without departing fromthe scope of the appended claims. Therefore, all embodiments that comewithin the scope and spirit of the following claims and equivalentsthereto are claimed.

The invention claimed is:
 1. A tissue separating barrier, comprising: ananti-adhesion material having tissue anti-adhesion characteristics,wherein the anti-adhesion material comprises fatty acids cross-linkeddirectly to each other by an ester bond, wherein the anti-adhesionmaterial is bioabsorbable; and a tissue fixating material disposed on asurface of the anti-adhesion material; wherein the fatty acids are fishoil fatty acids: wherein the anti-adhesion material and the tissuefixating material form the tissue separating barrier in such a way thatthe tissue separating barrier is non-inflammatory and fixates to tissue,in vivo, for a duration of greater than 10 days; and wherein the tissuefixating material comprises carboxymethylcellulose (CMC).
 2. The tissueseparating barrier of claim 1, wherein the fish oil fatty acids of theanti-adhesion material comprises one or more omega-3 fatty acids.
 3. Thetissue separating barrier of claim 1, wherein the carboxymethylcellulose(CMC) is sodium carboxymethylcellulose (Na-CMC).
 4. The tissueseparating barrier of claim 1, wherein the anti-adhesion material is afilm and the tissue fixating material is disposed on only one side ofthe film.
 5. The tissue separating barrier of claim 1, wherein theanti-adhesion material reduces inflammation otherwise associated withthe tissue fixating material.
 6. The tissue separating barrier of claim1, further comprising a plasticizing agent.
 7. The tissue separatingbarrier of claim 6, wherein the plasticizing agent comprises one of agroup of glycerin, propylene glycol, poly ethylene glycol, triacetincitrate and triacetin.
 8. The tissue separating barrier of claim 1,wherein the anti-adhesion material further comprises a therapeuticagent.
 9. A tissue separating barrier, comprising: a film derived from afatty acid-derived biomaterial comprising a fish oil; and a tissuefixating material disposed throughout the film; wherein the filmcomprises fish oil fatty acids cross-linked directly to each other by anester bond; wherein the film and the tissue fixating material form thetissue separating barrier in such a way that the tissue separatingbarrier is non-inflammatory and fixates to tissue, in vivo, for aduration of greater than 10 days; and wherein the tissue fixatingmaterial comprises carboxymethylcellulose (CMC).
 10. The tissueseparating barrier of claim 9, wherein the tissue fixating materialfurther comprises a tissue fixating coating surrounding the film. 11.The tissue separating barrier of claim 9, wherein the film is an omega-3fatty acid based film.
 12. The tissue separating barrier of claim 9,wherein the carboxymethylcellulose (CMC) is sodiumcarboxymethylcellulose (Na-CMC).
 13. The tissue separating barrier ofclaim 4, wherein the fatty acid-derived biomaterial reduces inflammationotherwise associated with the tissue fixating material in absence of thefatty-acid based film.
 14. The tissue separating barrier of claim 9,wherein the tissue separating barrier has a residence time that issufficient to prevent post-surgical adhesions.
 15. The tissue separatingbarrier of claim 9, further comprising a plasticizing agent.
 16. Thetissue separating barrier of claim 15, wherein the plasticizing agent isselected from the group consisting of glycerin, propylene glycol, polyethylene glycol, triacetin citrate and triacetin.
 17. A method forpreparing a tissue separating barrier formed of a film having tissueanti-adhesion characteristics and a tissue fixating material in such away that the tissue separating barrier is non-inflammatory and fixatesto tissue, in vivo, for a duration of greater than 10 days, the methodcomprising: creating the film from fish oil, wherein the film comprisesfish oil fatty acids cross-linked directly to each other by an esterbond; providing the tissue fixating material; and combining the filmwith the tissue fixating material to form the tissue separating barrier;wherein the film is bioabsorbable; and wherein the tissue fixatingmaterial comprises carboxymethylcellulose (CMC).
 18. The method of claim17, wherein the carboxymethylcellulose (CMC) is sodiumcarboxymethylcellulose (Na-CMC).
 19. The method of claim 17, wherein thetissue fixating material is disposed on only one side of the film. 20.The method of claim 17, wherein the tissue fixating material coats thefatty-acid based film on more than one side of the fatty acid-basedfilm.
 21. The method of claim 17, wherein the tissue fixating materialis disposed throughout the fatty-acid based film.
 22. The method ofclaim 17, wherein the film reduces inflammation otherwise associatedwith the tissue fixating material.
 23. The method of claim 17, furthercomprising a step of providing a plasticizing agent.
 24. The method ofclaim 23, wherein the plasticizing agent comprises one of a group ofglycerin, propylene glycol, poly ethylene glycol, triacetin citrate andtriacetin.
 25. The method of claim 17, wherein the film furthercomprises a therapeutic agent.
 26. A tissue separating, comprising:fatty-acid based particles derived from a fatty acid-derived biomaterialcomprising fish oil; and an aqueous base solution comprising a tissuecoherent material, wherein the fatty-acid based particles comprise fishoil fatty acids cross-linked directly to each other by an ester bond;wherein the fatty-acid based particles are mixed with the aqueous basesolution to form the tissue separating barrier in such a way that thetissue separating barrier is non-inflammatory and coheres to tissue, invivo, for a duration of greater than 10 days; and wherein the tissuecoherent material comprises carboxymethylcellulose (CMC).
 27. The tissueseparating barrier of claim 26, wherein the fatty-acid based particlesare soaked in a therapeutic agent before being mixed with the aqueousbase solution.
 28. The tissue separating barrier of claim 26, wherein amean particle size of the fatty-acid based particles is between about 1micron and about 50 microns.
 29. The tissue separating barrier of claim28, wherein the mean particle size of the fatty-acid based particles isbetween about 1 micron and about 10 microns.
 30. The tissue separatingbarrier of claim 26, wherein the fatty-acid based particles have adistribution of size of about 1-20 μm.
 31. The tissue separating barrierof claim 26, wherein the fatty-acid based particles have a distributionof size of about 21-40 μm.
 32. The tissue separating barrier of claim26, wherein the fatty-acid based particles have a distribution of sizeof about 41-150 μm.
 33. The tissue separating barrier of claim 26,wherein the fatty-acid based particles are omega-3 fatty acid basedparticles.
 34. The tissue separating barrier of claim 26, wherein thecarboxymethylcellulose (CMC) is sodium carboxymethylcellulose (Na-CMC).35. A coating on a medical device, comprising: an anti-adhesionmaterial; and a tissue fixating material disposed onto or throughout theanti-adhesion material; wherein the anti-adhesion material comprisesfish oil fatty acids cross-linked directly to each other by an esterbond; wherein the anti-adhesion material is bioabsorbable; wherein thetissue fixating material comprises carboxymethylcellulose (CMC); whereinthe tissue fixating material is not cross-linked; and wherein thecoating fixates to tissue in vivo for a duration of at least 10 days.36. The coating of claim 35, wherein the tissue fixating materialfurther comprises a plasticizing agent.
 37. The coating of claim 36,wherein the plasticizing agent is selected from the group consisting ofglycerin, propylene glycol, poly ethylene glycol, triacetin citrate andtriacetin.
 38. The coating of claim 35, wherein the coating hasanti-adhesion characteristics.
 39. The coating of claim 35, wherein theanti-adhesion material comprises one or more omega-3 fatty acids. 40.The coating of claim 39, wherein the one or more omega-3 fatty acids areselected from the group consisting of eicosapentaenoic acid (EPA),docosahexanoic acid (DHA), alpha-linolenic acid (ALA) and combinationsthereof.
 41. The coating of claim 35, wherein the anti-adhesion materialfurther comprises fatty acids cross-linked to each other by lactonecross-links.
 42. The coating of claim 35, wherein thecarboxymethylcellulose (CMC) is sodium carboxymethylcellulose (Na-CMC).43. The coating of claim 42, wherein the fish oil further comprisesVitamin E.
 44. The coating of claim 35, wherein upon hydrolysis of thecoating substantially non-inflammatory products are produced.
 45. Thecoating of claim 35, wherein the medical device comprises one or more ofa surgical mesh, a graft, a catheter balloon, a stand-alone film, or astent.
 46. The coating of claim 35, wherein the medical device comprisesa surgical mesh.
 47. The tissue separating barrier of claim 35, whereinthe anti-adhesion material further comprises a therapeutic agent.
 48. Atissue separating barrier, comprising an emulsion base, wherein theemulsion base comprises an aqueous solution, carboxymethylcellulose,fish oil, and particles, wherein the particles are comprised of fish oilfatty acids cross-linked directly to each other by an ester bond, andwherein the tissue separating barrier is non-inflammatory and fixates totissue, in vivo, for a duration of greater than 10 days.